In 1989, interleukin-18 (IL-18) was regarded as interferon-γ (IFN-γ)-inducing factor (IGIF). Now, it is known that IL-18 is a proinflammatory cytokine having various functions in addition to the ability to induce interferon-γ. IL-18 has functions such as activation of NF-κB, expression of Fas ligand, induction of both CC and CXC chemokines, and increase in the production of competent human immunodeficiency virus. Since IL-18 has the ability to induce interferon-γ production in T cells and macrophages, it plays an important role in Th1-type immune response and participates both in congenital immunity and in acquired immunity. IL-18 is related to the IL-1 family both in terms of structures and in terms of functions. Reviews regarding the structure, functions, and biological activity of IL-18 have been made (e.g., Non Patent Literatures 1 to 5).
Intracellular pro-IL-18 is treated in a proteolytic manner by caspase 1 in endotoxin-stimulated cells (Non Patent Literatures 6 and 7) as well as by caspases 4, 5, and 6 in Fas-L or bacterial DNA-stimulated cells (Non Patent Literature 8) to become a 18 kDa active form. Pro-IL-18 is also activated in a proteolytic manner by other proteases including mast cell-derived chymase (Non Patent Literature 9), neutrophil proteinase 3 (Non Patent Literature 10), caspase 3 (Non Patent Literature 11), and elastase and cathepsin (Non Patent Literature 12), which are serine proteases. IL-18 in both humans and mice lacks a leader sequence, and the mechanism underlying mature IL-18 release from cells has not yet been elucidated sufficiently.
The biological activity of IL-18 is mediated by the binding of IL-18 to heterodimer IL-18 receptor (IL-18R) consisting of two subunits: α-subunit (one member of the IL-1R family also called IL-1R-related protein-1 or IL-1Rrp1) and β-subunit (also called IL-18R accessory protein, IL-18AP, or AcPL). The IL-18R α-subunit binds directly to IL-18, but cannot induce signal transduction. The IL-18R β-subunit does not bind to IL-18 in itself, but forms a high-affinity receptor (KD=approximately 0.3 nM) necessary for signal transduction, in collaboration with the α-subunit (Non Patent Literature 13). The IL-18 signal transduction mediated by the IL-18R αβ complex is similar to that of the IL-1R and toll-like receptor (TLR) system. The IL-18R signal transduction employs signal transduction molecules such as MyD88, IRAK, and TRAF6 to cause responses as in the case of IL-1, for example, activation of NIK, IκB kinase, NF-κB, JNK, and p38MAP kinase. It has been confirmed using IL-18Rα subunit (Non Patent Literature 14) and MyD88 (Non Patent Literature 15) or IRAK (Non Patent Literature 16) knockout variants that IL-18Rα and the signal transduction molecules, respectively, are necessary for the biological activity exhibition of IL-18.
Interstitial pneumonia (Non Patent Literature 17), adult-onset Still's disease (Non Patent Literature 18), chronic obstructive pulmonary disease (Non Patent Literature 19), metabolic bone disease (Patent Literature 1), multiple sclerosis (Non Patent Literature 5), diabetes mellitus (Non Patent Literature 5), ischemic kidney damage (Non Patent Literature 20), and the like have previously been reported as diseases with the overexpression of IL-18. Also, the overexpression of IL-18 is responsible for so-called Th1 diseases such as atopic dermatitis (Non Patent Literature 21) and serious organ damages in the liver and the intestine (Non Patent Literature 5).
In addition to these diseases, the involvement of IL-18 in the pathological conditions of bronchial asthma induced by Th1 cells and other various diseases has been pointed out.
The control of production or activity of IL-18 is very important as a therapy for such IL-18-dependent diseases or as a therapy for diseases whose onset is induced or which are exacerbated due to the excessive production of IL-18.